Estrogens, acting through the estrogen receptors, ER and ER, control many physiological and pathological processes in numerous target tissues. While progress has been made in developing ER ligands having more desirable patterns of selective activity, such as selective ER modulators (SERMs) and ER-subtype selective ligands, the diversity of modes and pathways through which the ERs act offers intriguing but as yet unexplored mechanisms through which one should be able to obtain new compounds having higher levels of desired selectivity. Our overall goal is to develop potent ER ligands optimized to deliver the full range of desired, long sought-after selectivity in three medically important areas, achieved by three distinct mechanisms: (A) brain neuroprotection mediated through ER with carefully selected ligands of novel structure; (B) cardiovascular protection afforded by selective activation of extranuclear-initiated ER signaling pathways by estrogen-dendrimer conjugates (EDCs) and small molecules of novel design; and (C) combined anti-proliferative/anti-inflammatory activity as optimized therapy for estrogen-dependent breast cancer and endometriosis, through unique ER conformations induced by structurally novel ligands. Each effort is centered on a distinct mechanistic paradigm and is supported by active, ongoing collaborations with established research groups that should lead to excellent opportunities for further pre-clinical development. Aims: (1) Develop Novel ER Ligands Having Selective Brain Neuroprotective Activities. A subset of our ER ligands, acting through an endogenous autocrine anti-inflammatory pathway, is neuroprotective and is active in animal models of multiple sclerosis, reversing established disease. We will develop structure-activity relationships to enhance potency and selectivity of these novel compounds. (2) Develop Novel Pathway-Specific ER Ligands that Afford Selective Vascular, Cardiac, and Bone Protection. Our EDC blocks hormone entry into the nucleus and activates only the extranuclear-initiated ER signaling pathway, yet it provides cardiovascular protection equivalent to that of estradiol without stimulation of uterus or breast tumors. We will develop orally active conjugates with highly stable dendrimers and carefully designed small molecules having pathway selectivity. (3) Develop Novel ER Ligands that Combine Anti- Inflammatory and Anti-Proliferative Activities for Improved Therapy for Endocrine-Resistant Breast Cancers and Endometriosis. Our 3-dimensional ER ligands stabilize a previously unseen ER conformation and inhibit hormone-resistant breast cancer lines and endometriotic lesions. Using structure-guided design, we will develop higher potency and more selective compounds.